Targets Of Pharmacological Treatment Clinical Substrate

Schizophrenia is characterized by a wide range of symptoms, accompanied by significant deficits in function and marked diminution in the quality of life. Since no cure currently exists, pharmacological treatment is directed at inducing and maintaining remission of various symptom dimensions. Treatment-relevant domains of pathology include positive symptoms (delusions, hallucinations, suspiciousness, disorganized thinking), negative symptoms (impoverished speech and thinking, lack of social drive, flatness of emotional expression, apathy), cognitive and neuropsychological dysfunction [average intelligence quotient (IQ) in schizophrenia is 80 to 84, with prominent memory and learning difficulties], and mood symptoms (depression, anxiety). Schizophrenia presents a unique set of symptoms in each individual affected, creating considerable diversity of clinical presentation. To a large extent, the unique features of each case are defined by the relative contribution of various domains to the overall picture of symptoms. The relative severity of symptoms within these domains varies across individuals, as also in the same individual over the course of illness. The diagnosis of schizophrenia is typically made at the time of development of frank psychotic symptoms.

These symptom domains contribute differentially to impairments in function, with the severity of negative and cognitive symptoms most strongly correlated with degree of functional impairment. Pharmacological treatment is directed at the different symptom domains with the objective of reducing the severity of these symptoms and thereby improving function and quality of life. While pharmacological treatment of schizophrenia does improve each of the different psychopathological domains to varying extents, side effects associated with such treatment can worsen some symptom domains and can also independently have an adverse impact on function and quality of life. Additionally, side effects [particularly extrapyramidal symptoms (EPS)] contribute to treatment noncompliance, leading in turn to a worse course of illness; medication-free patients are three times as likely to relapse as adequately medicated patients. Consequently, the optimal pharmacotherapy of schizophrenia is one that provides the best possible control of the various symptoms while minimizing side effects from such treatment.

Active psychosis is the most common cause of hospital admission and as such is evidence of poor symptom control and relapse. A primary goal of pharmaco-logic treatment in schizophrenia is the elimination or reduction of positive symptoms.

Control of these symptoms is remarkably effective in reducing the need for inpatient treatment, thereby allowing patients to remain in community settings. All antipsychotics are effective in the treatment of positive symptoms. Negative symptoms can improve or worsen (because of parkinsonian side effects) with antipsychotic treatment (Miller and Tandon, 2000). Even with optimal antipsychotic treatment, negative symptoms tend to be present throughout the course of schizophrenia, including the premorbid and remission phases of the illness. This combination of pervasiveness, modest response to treatment, and enormous impact on quality of life make them a major challenge in the treatment of schizophrenia. Similarly, impaired cognition may be a primary symptom of the illness or may be a consequence of pharmacological treatment. The anticholinergic properties that are a prominent feature of many antipsy-chotics contribute directly to cognitive impairment, as do parkinsonian side effects (bradyphrenia) (Casey, 1995; Bilder, 1997; Harvey and Keefe, 1997). The frequent use of adjunctive anticholinergic agents to treat or prevent parkinsonian side effects further exacerbates secondary cognitive impairment, especially difficulties with memory (Tandon, 1999).

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